Adv Ther (2012) 29(6):551–561.DOI 10.1007/s12325-012-0028-6

ORIGINAL RESEARCH

Are Dosing Adjustments Required for Colchicine in the Elderly Compared with Younger Patients?

Suman Wason · Robert D. Faulkner · Matthew W. Davis

To view enhanced content go to www.advancesintherapy.comReceived: May 11, 2012 / Published online: June 29, 2012© The Author(s) 2012. This article is published with open access at Springerlink.com

ABSTRACT

Introduction: The objective of this study was to

compare the relative bioavailability of the US Food

and Drug Administration-approved formulation

of colchicine after a single 0.6 mg dose in young

(18–30 years of age) and elderly (≥60 years of age)

healthy subjects to determine whether dosing

adjustments are required in elderly patients.

Methods: A single-dose, single-drug, parallel-

group study was performed in 20 young subjects

with normal renal function (defined as creatinine

clearance [CrCl] ≥80 mL/min) and 18 elderly

subjects with normal or mild renal impairment

(CrCl ≥50 mL/min) in otherwise good health.

Blood samples were collected for up to 72 hours

postdose and analyzed for colchicine using a

validated liquid chromatography/tandem mass

spectrometry method. Noncompartmental

pharmacokinetic parameters were compared

using analysis of variance methods.

Results: There were no statistically significant

(P < 0.05) differences in mean colchicine

pharmacokinetic parameters between young

and elderly subjects, including peak plasma

concentration (Cmax) (2.53 vs. 2.56 ng/mL),

time to Cmax (1.25 vs. 1.25 hours), area under

the plasma concentration-time curve to infinity

(22.29 vs. 25.01 ng/h/mL), elimination half-life

(25.4 vs. 30.1 hours), oral clearance (0.40 vs.

0.35 L/h/kg), and apparent volume of

distribution (14.3 vs. 14.8 L/kg), respectively.

Conclusion: The lack of any significant

differences in colchicine pharmacokinetic

parameters between young and elderly healthy

subjects, with some of the latter including

mild renal impairment, suggests that dose

modification of colchicine may not be necessary

in healthy elderly patients. However, when

evaluating the use of colchicine dosing in an

elderly patient, the confounding effect on

overall exposure and safety from comorbid

conditions, the use of concomitant medications,

and the administration of multiple doses should

be considered.

ClinicalTrials.Gov #NCT01001052.

S. Wason (*) · R. D. Faulkner · M. W. Davis URL Pharma, Inc., Mutual Pharmaceutical Company, Inc., 7722 Dungan Road, Philadelphia, PA 19111, USA e-mail: swason@urlpharma.com

Enhanced content for Advances in Therapy articles is available on the journal web site: www.advancesintherapy.com

552 Adv Ther (2012) 29(6):551–561.

triphosphate-dependent phosphoglycoprotein

that is located in the cell membranes of

numerous tissues, is responsible for the efflux

of colchicine across membranes, including

within enterocytes of the intestine. P-gp plays a

predominant role in the incomplete absorption

of colchicine (mean absolute bioavailability

is approximately 45%), the enterohepatic

recirculation that occurs as evidenced by

secondary peak plasma concentrations and for

many potential drug–drug interactions (e.g.,

cyclosporin) [5, 6].

Colchicine also undergoes hepatic

biotransformation by cytochrome 3A4

(CYP3A4) to form three minor metabolites

(2-O-demethylcolchicine, 3-O-demethylcolchicine,

and 10-O-demethylcolchicine) that account for

less than 5% of the parent compound in human

plasma [4]. CYP3A4 inhibition of colchicine by

certain drugs (e.g., macrolides, statins) has the

potential to induce colchicine toxicity by dual

modulation of both P-gp and CYP3A4 [6].

There is little information on the

potential effect of age, gender, or race on the

pharmacokinetics of colchicine. A published

study investigated the pharmacokinetics of

colchicine in six healthy young men and four

elderly women after single-dose administration

intravenously (i.v.) (0.5 mg in young men and

1 mg in elderly women) and orally (1 mg in each

group) [8]. Mean absolute bioavailability was

similar in the young men and elderly women

(44% vs. 45%, respectively), whereas peak plasma

concentration (Cmax) was approximately twofold

higher in the elderly women compared with

the young men (5.5 vs. 12 ng/mL). Following

i.v. administration, the volume of distribution

at steady state (4.2 vs. 2.9 L/kg) and total body

clearance (10.5 vs. 5.5 L/h) were reduced in the

elderly women.

The pharmacokinetics of the currently

approved formulation of colchicine have been

Keywords: Age; Bioavailability; Colchicine;

Dosing; Pharmacokinetics

INTRODUCTION

The prevalence of gout is increasing due to

various factors, including the aging population

and dietary/lifestyle changes [1, 2]. The National

Health and Nutrition Examination Survey

(NHANES) estimated the prevalence of gout in

the US population between 2007 and 2008 to

be 8.3 million adults (≥20 years of age), affecting

6.1 million men (5.9% of the population) and

2.2 million women (2.0% of the population) [3].

The overall prevalence of gout has increased from

2.7% (NHANES III, 1988–1994) to 3.9% (NHANES,

2007–2008) [3].

Colchicine 0.6 mg is indicated for the

prophylaxis and treatment of acute gout

attacks in adults and the treatment of familial

Mediterranean fever in adults and children

4 years of age and older [4]. There is limited

information on the effect of age on the

pharmacokinetics of colchicine.

Colchicine binds to β-tubulin heterodimers

that comprise microtubules, disrupting the

cytoskeleton and inducing various signaling

pathways and cellular events, eventually

resulting in its anti-inflammatory mechanism

of action in the treatment of gout [5, 6].

Although the exact mechanism has not been

completely elucidated, colchicine inhibits the

inflammasome complex in neutrophils and

monocytes, interfering with the activation of the

proinflammatory cytokine interleukin-1β [7]. The

ubiquitous nature of microtubules contributes

to the apparent volume of distribution (Vd/F)

of colchicine, which greatly exceeds total body

volume, and the slow dissociation half-life (T1/2)

of the tubulin–colchicine complex (20–30 hours)

contributes to the prolonged plasma elimination

half-life [5]. P-glycoprotein (P-gp), the adenosine

Adv Ther (2012) 29(6):551–561. 553

history of psychiatric disorders within the

previous 2 years that required hospitalization

or medication; use of pharmacologic agents

known to induce or inhibit drug-metabolizing

enzymes (especially CYP3A4) within 30 days

before dosing; use of a study drug in a research

investigation within 30 days before dosing;

history of treatment for drug or alcohol

addiction, or excessive alcohol consumption

(>14 units/week on average) within the previous

year; positive test result for drug abuse; use of

tobacco products within 90 days before dosing;

positive HIV, hepatitis B surface antigen, or

hepatitis C antibody test; difficulty in fasting or

eating standard meals; donation or significant

loss of whole blood (≥480 mL) within 30 days

or plasma within 14 days before dosing;

inability or unwillingness to tolerate multiple

venipuncture; and women with a positive

serum pregnancy test result, who were likely to

become pregnant during the study, or who were

lactating. Furthermore, women of childbearing

potential had to be prepared to abstain from

sexual intercourse or have used and continue to

use a reliable method of contraception (e.g., use

of condom with spermicide, intrauterine device,

hormonal contraception) 30 days before dosing

and throughout the study.

Study Design

The study protocol received ethics committee

approval (Novum Independent Institutional

Review Board). All subjects provided written

informed consent before study participation, which

was conducted in accordance with the US Code of

Federal Regulations and International Conference

on Harmonisation Guidelines for Good Clinical

Practice, and adhered to the ethical principles of the

Declaration of Helsinki. The study was performed

at a single study center (Novum Pharmaceutical

Research Services, Las Vegas, Nevada, USA).

reported in the US prescribing information [4],

reviews [5, 9], and studies in young subjects [10, 11],

but the potential effect of age per se on drug

disposition of this formulation has not been

formally investigated until now. The objective of

this study was to compare the pharmacokinetics

of colchicine following the oral administration of

a single 0.6 mg tablet of the approved colchicine

formulation when given to young (18–30 years

of age) and elderly (≥60 years of age) healthy

subjects following an overnight fast.

METHODS

Subjects

Adult male and female subjects with a body mass

index of 18–30 kg/m2 who were either young

(18–30 years of age) or elderly (>60 years of age)

were eligible for recruitment if they were in good

health on the basis of medical history, physical

examination, and routine laboratory tests. Elderly

subjects with normal renal function (defined as

creatinine clearance [CrCl] ≥80 mL/min) or with

mild renal impairment (defined as CrCl between

50 and 80 mL/min) were allowed to participate,

whereas young subjects were required to have

normal renal function. The Cockcroft–Gault

formula was used to measure CrCl.

Exclusion criteria included history of allergy

or sensitivity to colchicine; history of any

drug hypersensitivity or intolerance likely to

compromise the safety of the subject or the

study in the investigator’s opinion; significant

history or current evidence of chronic infectious

disease, system disorders, organ dysfunction

(especially cardiovascular disorders), stroke,

renal or hepatic disorder, diabetes, or bleeding

disorders; presence of gastrointestinal disease or

history of malabsorption in the previous year;

presence of any medical condition requiring

regular treatment or prescription drug treatment;

554 Adv Ther (2012) 29(6):551–561.

Following a screening period of up to

4 weeks, all subjects received a single 0.6 mg

colchicine tablet administered with 240 mL of

water at room temperature. They were instructed

to swallow the tablet whole without chewing or

biting. Dosing order was randomly assigned by

age group in blocks of two.

All subjects checked into the clinical

investigation facility on day 1 with an evening

meal served and consumed more than 10 hours

before dosing. No food or beverages (except

water) were permitted until 4 hours after study-

drug administration on day 1. Standardized meals

and snacks were served at approximately 4, 9,

and 13 hours after dosing during confinement

in the test facility. Blood sample collections were

performed before meals if sampling and meal

times coincided. No caffeine, xanthine, alcohol,

or grapefruit products were permitted during

confinement; subjects were also instructed to

abstain from any food or beverages containing

these products within 48 hours before dosing and

throughout the period of blood sample collection.

During the confinement period of the study,

additional fluids were not permitted from 1 hour

before to 1 hour after dosing except for the water

administered with the test dose. Otherwise, water

was freely encouraged, although no fluids other

than water or those served with standardized

meals were permitted. Subjects left the clinical

facility approximately 24 hours after test dose

administration (day 2) but returned to provide 36,

48, 60, and 72-hour blood sample collections.

Subjects were not permitted to take

prescription medications except for hormonal

contraception within 2 weeks before dosing

and over-the-counter medications including

vitamins and herbal products within 3 days

before dosing and throughout the duration of

blood sample collection.

Subjects were advised that they could withdraw

from the study at any time for any reason.

Furthermore, the investigator could withdraw

subjects from the study to protect their health or

for noncompliance with study procedures. Any

subject experiencing vomiting within 3 hours

after dosing (based on twice the expected time

to Cmax [Tmax] of ~1.5 hours) would be dropped

from analysis. No subjects were discontinued

because of these criteria.

Medical history, physical examination,

12-lead electrocardiography, routine laboratory

tests, drug screen, virology tests for HIV and

hepatitis viruses, and serum pregnancy test were

performed during the 4-week screening period.

Vital signs were measured during the screening

period and on days –1, 1, and 2, with regular

testing on day 1 before dosing and at regular

intervals after dosing. Urine pregnancy test and

repeat drug screen were performed on admission

to the clinical facility on day –1. Medical history

was reviewed again on day 2, on days 3–4, and

on discharge from the clinical facility. Routine

laboratory tests were also repeated at discharge

from the clinical facility. Any undesirable sign,

symptom, or medical condition occurring

after starting the study, whether reported

spontaneously, in response to questioning, or

directly observed, was recorded regardless of

suspected relation to the study medication.

All treatment-emergent adverse events (AEs)

were recorded (coded using MedDRA version

12.0 adverse event dictionary) and were graded

by intensity (mild, moderate, or severe) and

relationship to the study drug (unlikely, possible,

or probable) by the investigator.

Pharmacokinetic Measurements

Venous blood samples (6 mL in prechilled EDTA

tubes) were taken by direct venipuncture at

0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9,

10, 11, 12, 16, 18, 24, 36, 48, 60, and 72 hours

postdose. Samples were mixed by gently inverting

Adv Ther (2012) 29(6):551–561. 555

the tubes several times and centrifuged at

approximately 2,700–3,000 rpm for 10 minutes

at 4°C. Plasma samples were collected into

polypropylene tubes and stored frozen to at

least –18°C until analysis. The time from blood

collection to being centrifuged was less than

60 minutes and to plasma being frozen was less

than 120 minutes. Frozen plasma samples on

dry ice were transported overnight for assay at a

single analytical laboratory (Frontage Laboratories,

Inc, Malvern, Pennsylvania, USA) using a liquid

chromatography/tandem mass spectrometry (LC/

MS/MS) method. For assay, 100 µL of thawed

plasma was mixed with 20 µL of diluent 1

(methanol/water, 50:50), 20 µL of internal standard

(colchicine-d3 5 ng/mL), and 300 µL of diluent 2

(ammonium formate 400 nmol/L in water). Then,

1.5 mL of extraction solvent (methyl tert-butyl

ether/ethyl acetate, 60:40) was added, mixed for

10 minutes, and centrifuged for 5 minutes at

3,000 rpm. The organic layer was removed, dried

at 35°C under nitrogen using an evaporator for

approximately 20 minutes, and reconstituted in

200 µL of mobile phase (methanol/ethyl acetate,

60:40, with ammonium formate 2 mmol/L).

A 20-µL aliquot was injected (Shimadzu liquid

chromatography pump and autosampler) onto

LC/MS/MS (Sciex API 5000). A Synergi Polar-RP,

50 × 2.0 mm, 4-µm column was used with a pump

flow rate of 0.6 mL/min. Analysis was performed

in positive ionization mode, with colchicine

and internal standard identified by the multiple

reaction monitoring transitions m/z 400.2 → 310.1

and m/z 402.1 → 310.1, respectively. The assay

calibration range was 0.02–20 ng/mL for analytical

runs with a lower limit of quantitation of

0.02 ng/mL. Intraday accuracy was 99.1–110.0%

with intraday precision of 2.35–17.54 coefficient

of variation (%CV), and interbatch accuracy was

99.17–100.05% (1.92–13.32 %CV).

Model-independent pharmacokinetic

parameters for colchicine were determined

using the SAS (version 9.1.3 or later), including

Cmax; Tmax; AUC0–t (area under the plasma

concentration-time curve [AUC] from time

zero to time t, where t is the time of the last

measurable concentration [Ct] calculated using

the linear trapezoidal method); AUC0–∞ (AUC

from time zero extrapolated to infinity calculated

as AUC0–t + Ct/Kel, where Ct is the last measurable

drug concentration and Kel is the elimination rate

constant estimated via linear regression of the

terminal portion of the log concentration versus

time curve); T1/2 (elimination half-life calculated

as ln[2]/Kel); CL/F (apparent clearance calculated

as the dose/AUC0–t); and Vd/F (apparent volume

of distribution, calculated as CL/Kel).

Statistical Analysis

Descriptive statistics (mean ± SD) were used

to summarize the pharmacokinetic data for

each age group. Analyses of variance (ANOVA)

were performed using the general linear model

procedure of SAS (version 9.1.3 or later) with

hypothesis testing for study-drug effects at

α = 0.05. The statistical model contained the

main effect of group. Least square means for the

groups (LSMEANS statement), the differences

between adjusted group means, and the

standard errors associated with these differences

(ESTIMATE statement) were calculated.

Comparison of Cmax, AUC0–t, and AUC0–∞ 90%

confidence intervals (CI) for each group was

constructed to test two one-sided hypotheses

at the α = 0.05 level of significance, with

confidence intervals presented for the geometric

mean ratios obtained from logarithmic (ln)-

transformed data. In addition, the relationship

between colchicine pharmacokinetic parameters

and covariates including age and CrCl were

investigated by linear regression analysis.

Post-hoc analysis of differences in race and

gender (n = 38) was also performed.

556 Adv Ther (2012) 29(6):551–561.

RESULTS

Baseline demographic and clinical characteristics

for the 38 subjects (20 young and 18 elderly;

20 women and 18 men; 14 African American,

15 white, and 9 “other”) included in the

statistical analysis are summarized in Table 1.

Elderly subjects in this study had a median age

of 62 years and a mean age of 62.8 ± 2.83 years.

No subjects older than 70 years were enrolled

in the study. The age groups were balanced

for weight and body mass index. There were

significant differences in mean age (P < 0.001)

and CrCl (P < 0.001) between the young

and elderly groups. There was a statistically

significant difference (P < 0.001) in CrCl between

age groups (132 ± 23.2 mL/min for young

vs. 87.0 ± 17.9 mL/min for elderly subjects).

Table 1 Baseline demographic and clinical characteristics

Characteristic Young subjects Elderly subjects

(n = 20) (n = 18)

Gender, n (%)

Male 8 (40.0) 10 (55.6)

Female 12 (60.0) 8 (44.4)

Ethnicity, n (%)

Hispanic 4 (20.0) 3 (16.7)

Non-Hispanic 16 (80.0) 15 (83.3)

Race, n (%)

American Indian or Alaska Native 0 2 (11.1)

Black or African American 13 (65.0) 1 (5.6)

White 3 (15.0) 12 (66.7)

Other 4 (23.5) 3 (16.7)

Median age, year (range) 25 (18–30) 62 (60–70)

Mean age, year ± SD 24.41 ± 3.66* 62.83 ± 2.83*

Median height, cm (range) 172.2 (154.9–188.0) 167.6 (152.4–180.3)

Mean height, cm ± SD 67.29 ± 3.62 65.50 ± 3.42

Median weight, kg (range) 80.3 (52.6–95.3) 71.2 (61.2–92.5)

Mean weight, kg ± SD 170.53 ± 26.20 162.94 ± 21.69

Median body mass index, kg/m2 (range) 25.8 (20.4–29.9) 27.6 (20.4–30.0)

Mean body mass index, kg/m2 ± SD 26.19 ± 2.81 26.54 ± 3.19

Median CrCl, mL/min (range) 123 (83–183)* 86.0 (57–120)*

Mean CrCl, mL/min ± SD 132.56 ± 23.16* 87.02 ± 17.92*

CrCl creatinine clearance* P < 0.001 between groups

Adv Ther (2012) 29(6):551–561. 557

ratio for women to men was 1.21, a difference

deemed not clinically meaningful. The mean

Cmax for colchicine was similar in the young and

elderly groups (2.61 vs. 2.56 ng/mL, respectively).

Race was predominantly black among the

young subjects and white among the elderly

subjects, with a significant between-group

difference (P < 0.001). All 38 subjects were

evaluated for safety.

Mean plasma concentration-time profiles for

colchicine in the young and elderly subjects are

graphically presented in Fig. 1. The arithmetic

mean pharmacokinetic parameters for colchicine

in the young and elderly groups are summarized

in Table 2. Statistical comparisons revealed no

statistically significant (P < 0.05) differences

between the age groups for any of the colchicine

pharmacokinetic parameters.

The relationship between exposure to colchicine

(AUC) and CrCl is presented graphically in Fig. 2.

A trend for higher colchicine systemic exposure

with decreasing renal function (as measured by

CrCl) was seen; however, the magnitude of the

differences was small and not clinically meaningful.

With regard to gender, there was a significant

difference (P < 0.05) in AUCs; however, the mean

Table 2 Arithmetic mean pharmacokinetic parameters by age group for colchicine administered as a single 0.6-mg tablet to healthy subjects (n = 38)

Parameter Arithmetic mean ± SD (%CV) P value for between-group comparison Young Elderly

(n = 20) (n = 18)

AUC0–t (ng/h/mL) 19.95 ± 5.86 (29.4) 21.88 ± 6.22 (28.4) 0.3311

AUC0–∞ (ng/h/mL) 22.39 ± 6.95 (31.3) 25.01 ± 6.92 (27.7) 0.2352

Cmax (ng/mL) 2.61 ± 0.71 (27.6) 2.56 ± 0.97 (38.0) 0.9237

Tmax (h) 1.38 ± 0.42 (39.6) 1.25 ± 0.43 (34.3) 0.9869

Kel (h–1) 0.028 ± 0.006 (20.3) 0.025 ± 0.01 (28.7) 0.1459

T1/2 (h) 24.9 ± 5.34 (20.6) 30.06 ± 10.78 (35.9) 0.0936

CL/F (L/h/kg) 0.400 ± 0.121 (30.1) 0.351 ± 0.10 (29.0) 0.1876

Vd/F (L/kg) 14.3 ± 4.31 (30.0) 14.8 ± 5.59 (37.8) 0.7854

AUC0–t area under the plasma concentration-time curve to the last measurable time point, AUC0–∞ area under the plasma concentration-time curve to time infinity, Cmax peak plasma concentration, %CV coefficient of variation, Tmax time to reach Cmax, Kel elimination rate constant, t1/2 terminal half-life, CL/F apparent clearance, Vd/F apparent volume of distribution

Fig. 1 Mean plasma colchicine concentrations following oral administration of a single 0.6 mg colchicine tablet to young (l) and elderly (o) subjects

3

2

1

00 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

Mea

n co

lchi

cine

conc

entr

atio

n (n

g/m

L)

Time post-dose (hours)

558 Adv Ther (2012) 29(6):551–561.

The Cmax ratio (elderly/young) for colchicine

was close to unity (0.989 [90% CI 0.81–1.16]).

The AUC0–t and AUC0–∞ ratios for colchicine

were slightly less than unity (0.91 [90% CI

0.76–1.06] and 0.89 [90% CI 0.74–1.04],

respectively), indicating marginally higher

exposure to colchicine in the elderly patients,

although the difference was not significant

(P > 0.05). The mean elimination T1/2 was

slightly longer in subjects aged 60 years and

older than in those 18–30 years of age; however,

this was not significant (P > 0.05). Furthermore,

there were no differences in oral clearance (CL/F;

P > 0.05) or apparent volume of distribution (Vd/F;

P = 0.7854) between age groups.

Table 3 Study-drug emergent adverse events (n = 38)

AE Subjects, n (%)

Young Elderly

(n = 20) (n = 18)

Any AE 7 (35.0) 8 (44.4)

AE by preferred terma

Increased BPb 1 (5.0) 7 (38.9)

Somnolencec 1 (5.0) 2 (11.1)

Headachec 2 (10.0) 0

Tinnitusc 0 1 (5.6)

Abdominal discomfortc 1 (5.0) 0

Abdominal pain (upper)c 1 (5.0) 0

Nauseac 1 (5.0) 0

Feeling hotc 0 1 (5.6)

BP decreasedb 1 (5.0) 0

Heart rate increasedb 1 (5.0) 0

Dizzinessc 0 1 (5.6)

Nasal congestionb 1 (5.0) 0

AE adverse event, BP blood pressurea According to MedDRA version 12.0b Relationship to drug unlikelyc Relationship to drug possible

Fig. 2 Colchicine exposure (AUC) versus creatinine clearance. AUC area under the plasma concentration-time curve

50

45

40

35

30

25

20

15

10

5

0200

AU

C0-

inf (n

g/h/

mL)

Creatinine clearance(mL/min)

0 20 40 60 80 100 120 140 160 180

Adv Ther (2012) 29(6):551–561. 559

ANOVA comparisons by gender showed

slightly higher Cmax (2.76 vs. 2.38 ng/mL) and

AUC (26.2 vs. 21.7 ng/h/mL) in female subjects,

differences that were not statistically significant

(P > 0.05). Furthermore, no significant gender

differences were seen in Tmax, AUC, CL/F, Vd/F,

or T1/2. There were no significant differences in

colchicine pharmacokinetic parameters between

the racial groups.

A total of 15 of the 38 subjects reported

22 treatment-emergent AEs, with seven in the

young group and eight in the elderly group (Table 3).

None of the AEs was considered serious. All

22 AEs were classified as mild in intensity and

resolved spontaneously before study completion.

The AE relationship to drug was considered

unlikely (n = 11) or possible (n = 11). The most

frequent AEs were increased blood pressure

(n = 8) and somnolence (n = 3). The occurrence

of gastrointestinal disturbances related to therapy

with multiple doses of colchicine is typically

higher (26% in a clinical trial of patients with

acute gout flare) [4] than was reported in this

single-dose study of colchicine (5%). This same

clinical study does not, however, account for

the rate of increased blood pressures observed

in the present study (5% young subjects [n = 1]

and 38.9% elderly subjects [n = 7]) [4]. For the

occurrence of increased blood pressure, it was

determined that a relationship to study drug in

this study was unlikely.

DISCUSSION

The study sought to compare the relative

bioavailability of the US Food and Drug

Administration (FDA)-approved formulation

of colchicine after a single 0.6 mg dose in

young (18–30 years of age) and elderly healthy

subjects (≥60 years of age) to determine

whether dosing adjustments are required in

elderly patients. There were two identifiable,

potential limitations to this study. First, the age

of the elderly population was limited to a range

of 60–70 years to avoid potential confounding

issues of renal dysfunction. Second, the study

evaluated only healthy subjects without

comorbid conditions, such as gout, because

FDA guidance on drug–drug interaction studies

indicate that it is reasonable to study healthy

volunteers. In addition, elderly patients

with mild renal impairment were allowed to

participate at the discretion of the investigator

because they are generally considered to be

healthy and adjustment of dosing is not required

for treatment of gout flare, prophylaxis of gout

flare, and familial Mediterranean fever. However,

patients should be monitored closely [4].

Single-dose colchicine 0.6 mg was well

tolerated in young and elderly healthy subjects.

There were no clinically meaningful differences in

colchicine pharmacokinetic parameters (i.e., Cmax,

AUC, T1/2, and CL/F) between young and elderly

healthy subjects, including those with mild renal

impairment. In addition, there were no statistically

significant differences (P < 0.05) observed in the

comparisons of the pharmacokinetic parameters

by race or gender. Although the study was not

designed to examine gender or race differences in

colchicine pharmacokinetics, comparisons were

performed on the pooled data across the two age

groups by gender and race.

CONCLUSION

The only previous recommendation for colchicine

dosing was reported by Terkeltaub [12], who

suggested that the recommended maintenance

dose of colchicine should be reduced by half in

patients 70 years of age or older. These data were

empirical and not based on actual study results.

In this study, the lack of any clinically

meaningful differences in colchicine

pharmacokinetic parameters between healthy

560 Adv Ther (2012) 29(6):551–561.

young and elderly subjects, with some of the

latter having mild renal impairment, suggests

that dose modification of colchicine according

to age may not be necessary in adults. These

findings require confirmation in patients

with gout and, in general, dose selection

for colchicine in elderly patients with gout

should be performed with caution, taking

into consideration the presence of comorbid

conditions, concomitant medications, and

multiple doses.

ACKNOWLEDGMENTS

This is a PRISM publication. Mutual

Pharmaceutical Company’s PRISM (PRogram

to Improve the Safety of Medication) research

initiative provides for improvement of a

product’s safety profile and lifecycle management

by focusing on metabolic pathways, thereby

identifying methods for optimizing safety and

patient outcomes regardless of drug class. PRISM

discoveries provide valuable information to the

physician, pharmacist, and patient, and are

incorporated into the product label as required

by FDA guidance.

Dr. Wason is the guarantor for this article,

and takes responsibility for the integrity of the

work as a whole.

Medical editorial assistance was provided

by Peter Todd, PhD, and James A. Shiffer, RPh,

CCP, Write On Time Medical Communications,

LLC, and was funded by Mutual Pharmaceutical

Company, Inc., a wholly owned subsidiary of

URL Pharma, Inc. The authors acknowledge

Darin B. Brimhall, DO, CPI, from Novum

Pharmaceutical Research Services, located in Las

Vegas, NV, for his contribution as the principal

investigator for this study. The authors would

also like to acknowledge study leader and project

manager Kimberly Stulir, MBA, Robert Faulkner,

PhD, Thomas Lauterio, PhD, and Deborah

DeMaria, MS (Mutual Pharmaceutical Company,

Inc.) for their review and critical revisions for

important intellectual content.

Conflict of Interest. S.W. is employed by

Mutual Pharmaceutical Company, Inc., a wholly

owned subsidiary of URL Pharma, Inc., and holds

employee equity shares in the parent company.

R.D.F. is employed by Mutual Pharmaceutical

Company, Inc., a wholly owned subsidiary of

URL Pharma Inc., and holds employee equity

shares in the parent company. M.W.D. is

employed by Mutual Pharmaceutical Company,

Inc., a wholly owned subsidiary of URL Pharma,

Inc., and holds employee equity shares in the

parent company as well as 13 patents pertaining

to colchicine.

Funding Statement. Supported by Mutual

Pharmaceutical Company, Inc., a wholly owned

subsidiary of URL Pharma, Inc.

Open Access. This article is distributed

under the terms of the Creative Commons

Attribution Noncommercial License, which

permits any noncommercial use, distribution,

and reproduction in any medium, provided the

original author(s) and source are credited.

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